Abstract

Parkinson disease (PD) presents several features including the relative selective localisation of pathology to the substantia
nigra and well‐defined motor symptoms caused by dopaminergic degeneration that make it an ideal target for gene therapy. Parallel
progress in viral vector systems has made it possible to deliver therapeutic genes directly into the brain with reasonable
safety. To date, gene therapy for PD is mainly based on symptomatic approaches that involve enzyme‐replacement strategies
to restore dopamine (DA) levels or correct the functional perturbation of the basal ganglia caused by DA loss and disease‐modifying
approaches that depend on delivery of neurotrophic factors and alteration of genetic causes of PD to protect neuronal functions
and slow down or even halt disease progression. As supported by the increasing preclinical and clinical evidence, gene therapy
may be a promising treatment to relieve the disabling nature of PD.

Key Concepts:

Gene therapy for PD focusses on symptomatic approach that involves enzyme‐replacement strategy and disease‐modifying approach
that depends on addition of neurotrophic factors.

Intrastriatal expression of genes TH, AADC and GCH, the three key enzymes for DA biosynthesis, can compensate for the decreased
levels of DA in PD patients.

An approach aiming at modulating STN activity is done by delivering gene GAD, the rate‐limiting enzyme for GABA synthesis.

Neurotrophic factors including GDNF and NTN have potent trophic activity on dopaminergic neurons and play essential roles
in the protection and restoration of neuronal cells.